Disturbed Ca²⁺ Homeostasis in Muscle-Wasting Disorders

Ca²⁺ is essential for proper structure and function of skeletal muscle. It not only activates contraction and force development but also participates in multiple signaling pathways. Low levels of Ca²⁺ restrain muscle regeneration by limiting the fusion of satellite cells. Ironically, sustained elevations of Ca²⁺ also result in muscle degeneration as this ion promotes high rates of protein breakdown. Moreover, transforming growth factors (TGFs) which are well known for controlling muscle growth also regulate Ca²⁺ channels. Thus, therapies focused on changing levels of Ca²⁺ and TGFs are promising for treating muscle-wasting disorders. Three principal systems govern the homeostasis of Ca²⁺, namely, excitation-contraction (EC) coupling, excitation-coupled Ca²⁺ entry (ECCE), and store-operated Ca²⁺ entry (SOCE). Accordingly, alterations in these systems can lead to weakness and atrophy in many hereditary diseases, such as Brody disease, central core disease (CCD), tubular aggregate myopathy (TAM), myotonic dystrophy type 1 (MD1), oculopharyngeal muscular dystrophy (OPMD), and Duchenne muscular dystrophy (DMD). Here, the interrelationship between all these molecules and processes is reviewed.